BTK inhibitors and methods for their identification and use

Abstract

The invention provides BTK inhibitors, methods for their identification and use, and pharmaceutical compositions comprising BTK inhibitors.

We claim:  
     
       1. A method for inhibiting BTK activity, comprising contacting BTK or a cell that expresses BTK with a compound of formula I:                    
       where: 
       R 1  is (C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, or NR a R b ;  
       R 2  is hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyloxy amino (C 2 -C 5 )alkoxy; hydroxy (C 2 -C 5 )alkoxy amino (C 2 -C 5 )alkanoxy; or hydroxy (C 2 -C 5 )alkanoxy;  
       R 3  is cyano or (C 1 -C 3 )alkanoyl;  
       R 4  is hydrogen, (C 1 -C 3 )alkyl; hydroxy (C 2 -C 5 )alkyl; or amino (C 2 -C 5 )alkyl;  
       R 5  is phenyl substituted by —S(O) 2 R c , or by halo and at least one other substituent;  
       R a  and R b  are each independently hydrogen, or (C 1 -C 3 )alkyl; or R a  and R b  together with the nitrogen to which they are attached are pyrrolidino, piperidino, morpholino, or thiomorpholino;  
       wherein any phenyl of R 1  and R 5  is optionally substituted with one or more substituents independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, (C 1 -C 3 )alkoxy, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkanoyl, —S(O) 2 R c , or NR a R b ; wherein R c  is (C 1 -C 3 )alkyl, or aryl  
       or a pharmaceutically acceptable salt thereof.  
     
     
       2. A method according to claim  1 , wherein R 1  is C 1-3  alkyl, R 2  is hydroxy and R 3  is cyano. 
     
     
       3. A method according to claim  2 , wherein R 1  is methyl. 
     
     
       4. A therapeutic method according to claim  1 , wherein the BTK inhibitor has a structure selected from the group consisting of LFM-A13, LFM-A15, LFM-A16, LFM-A17, LFM-A18, LFM-A19, or LFM-A20, or a pharmaceutically acceptable salt thereof.